Micronized film-forming powder comprising an active substance

ABSTRACT

The present invention relates to a micronized film-forming powder having a particle size of at most 100 μm and comprising a combination of at least one active substance, at least one bioadhesive agent, and at least a plasticizer.

The present invention relates to a micronized film-forming powder,pharmaceutical, cosmetic or nutraceutical compositions containing thispowder, as well as to methods for their manufacture and their uses.

The micronized film-forming powder according to the present inventionpossesses the specific feature of forming a film in situ at the time ofits application on a moist or hydrated support. It can be applied to thedermis and/or to a mucous membrane.

Due to the fact that this powder forms a film on the dermis or on themucous membrane during its application, it allows the sustainedprolonged release of the active substance(s) which it contains. Thissustained release can occur in several ways. For example, linearly orwith a “burst effect” (immediate release of part of the activesubstance, followed by a sustained release), also called “bimodalrelease profile” or “rapid and sustained release effect”.

A decisive advantage of this galenic form consists in the fact that thefilm erodes with time so as to leave no residue.

Fluid compositions capable of forming films in situ during theirapplication are already known. Thus, patents U.S. Pat. No. 5,081,157 andU.S. Pat. No. 5,081,158, and patent applications WO 96/30000, WO97/31621, WO 00/10540, WO 00/38658, WO 01/13955 and WO 01/43722 describefilm-forming compositions for transdermal and/or transmucosalapplication. These compositions may be in the form of a solution, asuspension or a gel.

The film-forming compositions already known in the prior art suffer fromnumerous disadvantages. Among these, there may be mentioned thedifficulties of preparation linked to the production of compositionswhich can then form a homogeneous film, the difficulties of storingthese galenic forms because they are often unstable, and thedifficulties linked to their administration.

In particular, liquids, just like gels, are difficult to positionprecisely on the dermis or the mucous membranes, and tend to slide or tomove.

Moreover, many muco-adhesive preparations known in the state of the arthave such a thickness that they result in a discomfort for theindividual which uses them, especially when these preparations areapplied on buccal or vaginal mucosa.

Also, many preparations known in the state of the art, including thepatch type or wafer type preparations, comprise a support which stays inplace after the complete release of the active substance(s), whichrequires an intervention of the practicien to remove them, particularlyafter applying to the internal mucosa such as the vaginal mucosa.

The applicant companies have therefore sought to develop a galenic formwhich can overcome the disadvantages encountered by the earlierformulations.

They have thus succeeded in developing a micronized film-forming powderwhich has the properties of forming a cohesive continuous film when itis contacted with a hydrated or moist support, for example, with mucousmembranes or the previously hydrated skin. The film which is formedafter applying the micronized film-forming powder to the hydrated ormoist support has good adhesive and cohesion properties.

The film-forming composition in the form of a micronized powderaccording to the invention, unlike the fluid products of the prior art,does not require the use of any liquid carrier, especially solvents,during the administration of the product. This is quite obviously adecisive advantage for a product for pharmaceutical, cosmetic ornutraceutical use. The micronized powder form also allows a very goodstability of the product during storage, greater than that of productsin the form of solutions, suspensions or gels.

The micronized film-forming powder according to the present inventiontherefore has numerous advantages compared with galenic forms known inthe prior art.

Accordingly, the present invention relates to a micronized film-formingpowder having a particle size of at most 100 μm and comprising thecombination of at least one active substance, at least one biocompatibleadhesive agent, and at least one plasticizer.

By active substance, it is meant according to the invention anysubstance having a measurable activity, therapeutical, cosmetic ornutraceutical in nature, towards the human or animal body to which thissubstance is applied or administered.

By biocompatible adhesive agent, which may also be referred to as“bioadhesive agent”, it is meant according to the invention anysubstance or any compound which has the property of adhering to ahydrated or moist biological tissue when said substance or said compoundis applied to it, such as for example a mucous membrane or thepreviously hydrated dermis. To be biocompatible, the adhesive agent hasto be compatible with an use on the biological tissue, without causingunwanted reactions such as an inflammation of the biological tissue.

By plasticizer, it is meant any substance or any compound capable ofimproving the mechanical properties of the film formed from micronizedfilm-forming powder according to the invention in order to promote thephysical integrity of the film during its formation and to maintain thephysical integrity of the film after its formation, notably by promotingthe cohesion between the particles initially contained in the micronizedfilm-forming powder.

The micronized film-forming powder according to the invention has theproperties of forming a cohesive continuous film in contact with theaqueous medium. When said powder is contacted with a moist or hydratedsupport, preferably the mucous membranes or the previously hydrateddermis.

The film is formed very quickly, from the first minute after theapplication of the micronized film-forming powder to the surface of themoist or hydrated support, for example mucous membranes or previouslyhydrated dermis, as illustrated in the examples.

The particle size of the micronized film-forming powder according to theinvention is essential for obtaining a film which is cohesive andcontinuous throughout the surface of the support on which said powder isapplied.

Thus, a continuous and cohesive film having good adhesive properties isobtained on the hydrated or moist support with a micronized film-formingpowder as defined herein and having a particle size of at most 50 μm aswell as with a micronized film-forming powder having a particle size ofat most 20 μm, as described in the examples.

Excellent results were also obtained with a micronized film-formingpowder having a particle size close to 10 μm.

Accordingly, also being part of the invention is a micronizedfilm-forming powder having a particle size of at most 10 μm.

The micronized film-forming powder has a particle size of at least 0.01μm, preferably at least 0.1 μm and most preferably at least 1 μm.

Preferably, a micronized film-forming powder as defined above has aparticle size of between 0.01 μm and 100 μm, preferably between 0.1 μmand 70 μm and more preferably between 1 μm and 50 μm.

By “particle size” of a micronized film-forming powder according to theinvention, it is meant the mean size of the grains that constitute it.The mean size of the grains can be measured by any conventionaltechnique known per se. Notably, the persons skilled in the art can usea measure with the aid of a laser granulometry device of the BeckmanCoulter® or Malvern® type, as described in the examples.

The applicant has noticed that the grain size distribution of themicronized film-forming powder according to the invention follows anarrow Gauss curve, with the particle size value corresponding thereforeto the real size of the most part of the particles contained in saidpowder.

The micronized film-forming powder of the invention conveniently has aresidual humidity of between 0.1% and 10%, preferably between 2% and 8%,as measured with a humidity analyser type MA 30 sold by the SartoriusCompany and used in accordance with the manufacturer recommendations, asillustrated in the examples. The low relative humidity of the micronizedfilm-forming powder according to the invention allows for a storage timeof several months without affecting its particle size features nor itsproperties of forming a continuous and cohesive film when it is appliedto a moist or hydrated support.

Moreover, when the micronized film-forming powder according to theinvention is applied to a moist or hydrated support, the continuous and.cohesive film which is formed on the surface of the support has areduced thickness of between 10 μm and 1 mm, preferably between 50 μmand 400 μm and most preferably between 100 μm and 300 μm.

The low thickness of the continuous and cohesive film produced throughthe application of the micronized film-forming powder of the inventionavoids, or to say the least decreases, the discomfort sensationsexperienced with certain of the devices known earlier. Furthermore, thelow thickness of the film formed in this way, because of the lesser meandistance between the active substance(s) it contains and the targetsites of those active substances, for example the target sites locatedon the surface of a mucous membrane, allows an improved accessibility orbioavailability of the active substances towards their target sites andpromotes the release of all of the active substance(s)containedinitially in said film.

The adhesiveness of a film formed on a moist or a hydrated support fromthe micronized film-forming powder according to the invention isillustrated by the fact said film has an adhesiveness index or tack ofbetween 1N and 50N, preferably between 2N and 10N.

In order to measure the adhesiveness index or tack, the persons skilledin the art will conveniently use the so-called “Probe Tack” testperformed with a traction device, said test being defined in the ASTMstandard n° D 297901 (“Standard Test Method for Pressure-Sensitive Tackof Adhesives using an Inverted Probe Machine”—American Society forTesting and Materials), as illustrated in the examples.

The good properties of adhesion to the support of the film formed fromthe micronized film-forming powder according to the invention avoid, orto say the least decrease considerably the risks of detaching the filmfrom the support on which said film is formed or the risks of sliding ordisplacement of said film on the surface of the support, which furtherreduces the possible loss of active substance molecules which do notreach the intended target sites.

Finally, it was shown according to the invention that the film formedafter applying the micronized film-forming powder according to theinvention to a hydrated or moist support has a good resistance toliquids, which constitutes a technical feature particularly advantageousconsidering the surfaces on which said micronized film-forming powder islikely to be mostly applied, namely the mucous membranes and the dermis.The good resistance to liquids of said film allows to characterize it asa semipermeable film. The semipermeable character of the film formedfrom the micronized film-forming powder of the invention is illustratedby the fact that, while the contact angle of said film decreases withits exposition time to different types of liquids, no completeabsorption of these different types of liquids is seen whatever the pH,acid, basic or neutral, of the latter, as shown in the examples.

Generally, by allowing the formation in situ of a film having the abovetechnical features, the micronized film-forming powder according to theinvention allows a stabilization and a great effectiveness, includingtherapeutical, cosmetic an nutraceutical effectiveness, of the finalproduct.

Preferably, the micronized film-forming powder according to theinvention comprises, on the basis of the total weight of thecomposition, from 0.001% to 90% by weight of active substance(s), from1% to 90% by weight of biocompatible adhesive agent(s) and from 0.1% to30% by weight of plasticizer(s).

The persons skilled in the art adapt. the proportions of the differentcomponents of the micronized film-forming powder in accordance withconventional techniques for preparing galenic formulations such as forexample the one described in J. Control release: 61(1999) 175-183; J.Pharm (2000) 271-277, J. Control release.77 (2001) 1-6 and J. Pharm.Pharmacol. 48, 255 (1998), so that the powder might have the physical,mechanical and chemical features defined previously for the film formedfrom this powder, namely the thickness, adhesiveness index, resistanceto liquid and semipermeability features.

For example, for an active substance such as the iodedpolyvinylpyrrolidone, which is an active substance having by itselfadhesive properties, the micronized film-forming powder wild have a lowlevel of biocompatible adhesive agent.

The micronized film-forming powder according to the invention ischaracterized in that it may further comprise at least a compoundselected from a surfactant, a wetting agent, a binder, a retardant, apenetration enhancer, a bioerodible diluent, a colorant, a flavour, a pHcontrolling agent or a combination of at least two of these compounds.

The surfactants, wetting agents, binders, retardants, penetrationenhancers, other than those already acting as a biocompatible adhesiveagent or plasticizer, are added.

The active substances of the micronized film-forming powder according tothe invention may be selected from those conventionally used in thefollowing specialities: allergology, anaesthetic/intensive care,cancerology and haematology, cardiology and angiology, contraception andabortion, dermatology, endocrinology, gastroenterohepatology,gynaecology, immunology, infectiology, metabolism and nutrition,neurology/psychiatry, ophthalmology, ear, nose and throat, pneumology,rheumatology, stomatology, toxicology, urology/nephrology, and fromanalgesics and antispasmodics, anti-inflammatory agents, contrastproducts used in radiology, haemostatics, and products for treatingblood and derivatives. But also selected are all cosmetic and/ornutraceutical substances.

Advantageously, the active substances may be selected from the groupconsisting of the active substances crossing the skin barrier andreaching the systemic circulation, such as cyproterone acetate,Δ4androstenedione, 3-ketodesogestrel, desogestrel, gestodene, estradioland its derivatives, norethisterone acetate, progesterone, testosterone,trinitrine, fentanyl, nitroglycerine, nicotine (S(−)-nicotine),scopolamine, clonidine, isosorbide dinitrate, levonorgestrel incombination with ethinylestradiol or with estradiol, androstanolone,alclometasone dipropionate, and combinations thereof.

They may also be selected from the active substances crossing the skinbarrier and having a localized action such as: acetazolamide, acyclovir,adapalene, alclomethasone dipropionate, amcinonide, ameleine, bamethansulphate+escin, betamethasone valerate, betamethasone dipropionate,bufexamac, caffeine, calcipotriol monohydrate, cetrimonium bromide,clobetasol propionate, crilanomer, desonide, dexpanthenol, diclofenac,diflucortolone, valerate, difluprednate, diphenydramine hydrochloride,econazole nitrate, erythromycin, flumetasone pivalate, fluocinoloneacetonide, fluocinodine, fluocortolone, fluocortolone hexanoate,fluocortolone pivalate, hydrocortisone, hydrocortisone acetate,ibacitabin, ibuprofen, imiquimod, ketoconazole, ketoprofen, lidocaine,metronidazole, miconazole nitrate, minoxidil, niflumide acid,penciclovir, benzoyl peroxide, piroxam, iodinated povidone,promestriene, pyrazonibutasone, roxithromycin, sulphacetamide,triamconolone, tazarotene, tretinoin and isotretinoin, triclocarban,vidarabine monophosphate and combinations thereof.

They may also be selected from the following active substances:β₃-adrenergic agonist, growth hormone, oxybutinin, buprenorphine,pergolide, estradiol+nestorone, nestorone, 7α-methyl-19-nortesterone,mecamylamine (antagonist of nicotine)+nicotine, salbutamol, selegiline,buspirone, ketotifen, lidocaine, testosterone+estradiol, ketorolac,eptazocine, insulin, α-interferon, prostaglandines,17β-estradiol+norethindrone acetate, 5-aminolevulinic acid,benzodiazepine alprozolam, diclofenac, fenoprofen, flubiprofen,ketoprofen, methyl phenidate, miconazole, piroxicam, bruprenorphine,alprozolam, dexmedetomidine, prazosin (α-adrenergic antagonist),gestodene+ethinylestradiol, alprostadil, tulobuterol (β-adrenergicagonist), ethinylestradiol+norelgestromin, ketorolac, physostigmine,lidocaine, medindolol (α-adrenergic agonist), rotigotine (D2 dopamineantagonist), ethinylestradiol+norethindrone acetate, thiatolserine, andcombinations thereof.

They may also be selected from the active substances known to undergo aliver first pass effect such as:

-   -   17 β Estradiol, Molecules undergoing first pass effect (non        limiting)    -   17β Estradiol    -   Ethynylestradiol    -   Finasteride    -   Testosterone    -   Isotretinoin    -   Biphosphonates    -   Nicotine

They may also be selected from the active substances which undergo agastrointestinal degradation such as:

-   -   Omeprazole    -   Acamprosate    -   Sodium valmate    -   Esomeprazole magnesium trihydrate    -   Sodium diclofenac

They may also be selected from the active substances which have a lowbioavailability

The micronized film-forming powder may contain one or more activesubstances, combined with each other.

For cosmetic applications, the active substance may be chosen from thegroup comprising emollients, moisturizing agents, vitamins, complexes offruit amino acids, antioxidant agents and the like.

For nutraceutical applications, the active substance may be chosen fromthe group comprising vitamins, inorganic salts, brewers' yeast and thelike.

According to a preferred embodiment of the powder, according to theinvention, the active substances are micronized before being mixed withthe other ingredients. It is also possible to mix the nonmicronizedactive substance with the other ingredients of the powder and then tomicronize the final mixture. This promotes the homogeneity of the filmand the cohesion and adhesion of the particles on its applicationsupport. Moreover, systems for spraying powder are particularly wellsuited to the spraying of micronized products.

The bioadhesive agent of the micronized film-forming powder according tothe invention is advantageously selected from the group consisting ofethyl cellulose, methyl cellulose, carboxymethyl cellulose,carboxymethyl cellulose sodium, hydroxyethyl cellulose, hydroxypropylcellulose, hydroxypropyl methyl cellulose sodium, polyvinylpyrrolidone,polyvinyl alcohols, polyisobutylene, polyisopropene, xanthan gum, locustbean gum, chitosan, chitosan chloride, polycarboxylates, carbomers suchas carbopol, acrylic/methacrylic acid copolymer, acrylic acid/acrylamidecopolymer, acrylic acid/methyl methacrylate copolymer, acrylicacid/polyethylene glycol copolymer, polyacrylic acid/butyl acrylatecopolymer, HEMA (2-hydroxyethyl methacrylate) copolymerized withPolymeg® (polytetramethylene glycol), Cydot® marketed by 3M (carbopolcombined with polyisobutylene), pectin (of low viscosity), polyethyleneoxide, methyl vinyl ether/maleic anhydride copolymer, tragacanth,monomethyl ether, monomethacrylate, drum dried waxy maize starch, sodiumstearyl fumarate, sodium hyaluronate, guar gum, sodium alginate,starches, dextran and derivatives, and mixtures thereof.

The plasticizer of the micronized film-forming powder according to theinvention is conveniently selected from the group consisting of dibutylphthalate, dibutyl sebacate, acetyltributyl citrate, acetyltriethylcitrate, tributyl citrate, tributylethyl citrate, triacetin, PEG,propylene glycol, glycerol, glycerol monoesters and derivatives, castoroil and derivatives, and mixtures thereof.

The micronized film-forming powder according to the invention may alsocomprise one or more surfactants, which are preferably nonionic, such aspolyoxyethylene sorbitan (fatty acid ester, polyoxyethylene alkyl ether,polyoxyethylene derived from castor oil and derivatives, and mixturesthereof.

If necessary, the micronized film-forming powder may also comprise awetting agent selected from the group consisting of polyols such assorbitol, or glycerine, such as PEG and mixtures thereof.

The micronized film-forming powder according to the invention may alsocomprise a binder selected from the group consisting of acacia, alginicacid, carboxymethyl cellulose sodium, microcrystalline cellulose,dextrins, ethyl cellulose, gelatin, glucose, guar gum, hydroxypropylmethyl cellulose, methyl cellulose, polyethylene oxide, povidone,pregelatinized starch and derivatives, and mixtures thereof.

The micronized film-forming powder according to the invention may alsocomprise a hydrophilic or nonhydrophilic retardant selected from thegroup consisting of hydroxypropyl methyl cellulose acetate or succinate,hydroxypropyl methyl cellulose, hydroxypropyl cellulose, ethylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose sodium,polyvinyl alcohols, hydrocolloids such as: pectins, alginates, guar gum,xanthan gum, gum Arabic, agar, dextrin, carragheenan, polyethyleneoxide, carbomers, polymers and copolymers of acrylic acid, of methylmethacrylate, of polyvinyl acetate, of carboxymethyl acetate andmixtures thereof.

The micronized film-forming powder according to the invention may alsocomprise a bioerodible diluent selected from the group consisting ofcalcium or sodium carbonate or bicarbonate, sucrose, mannitol, xylitol,sorbitol, lactose, cellulose or microcrystalline cellulose powder,starch and its derivatives, dibasic calcium phosphate, tribasic calciumphosphate, calcium sulphate, dextrates, dextrins, dextrose excipients,fructose, kaolin, lactitol and mixtures thereof.

The micronized film-forming powder according to the invention may alsocomprise a penetration enhancers which may be selected from the groupconsisting of aliphatic fatty acid esters such as isopropyl myristate,fatty acids such as oleic acid; alcohols or polyols such as ethanol,propylene glycol and polyethylene glycol; components of essential oilsand terpenic derivatives (such as eugenoi, geraniol, nerol, eucaiyptoi,menthol); surfactants; moisturizers such as glycerin, urea; keratolyticssuch as alpha-hydroxy acids.

The micronized film-forming powder according to the invention may alsocomprise a colorant selected from the group comprising Curcumino,Lactoflavin (riboflavin), Tartrazin, Quinoline Yellow, Orange-Yellow S,Cochineal carminic acid Azorubine, Amaranth, Cochineal-red A BrillantBlue V, Indigotin (indigo carmine), Chlorophylls, Cupric complexes ofchlorophylls and chlorophyllins, Caramel, Black, Brillant BN, Carbomedicinalis vegetalis, Carotenoids, alpha, beta or gamma caroten, Bixin,Norbixin, (rocou Annatto), Capsantein, Capsorubin, Lykopene,Xanthophyils, Flavoxanthine, Lutein, Kryptoxanthine, Rubixanthine,Violoxanthine, Rhodoxanthine, Beet Red, Betanin, Anthocyanins, Calciumcarbonate, Titanum bioxide, Iron oxides or hydroxides, Aluminum, Silver,Gold.

The micronized film-forming powder according to the invention may alsocomprise a flavor selected from the flavors conventionally used inpharmacy.

The micronized film-forming powder according to the invention may alsocomprise a pH-controlling agent. The pH-controlling agents allow tostabilize or to promote the passage of the active substance(s) throughthe biological support on which the micronized film-forming powderaccording to the invention is applied. The pH-controlling agents cancontrol the thus formed film pH between pH 2.0 and pH 9.0.

Preferably, the pH-controlling agent is selected from the groupcomprising citric acid and its derivatives, phosphoric acid and itsderivatives, tartaric acid and its derivatives, bicarbonic acid and itsderivatives, or a combination of at least two of the abovepH-controlling agents.

The invention also relates to a pharmaceutical, cosmetic ornutraceutical composition comprising the micronized film-forming powderas defined in the present description. This composition may be appliedto the dermis or the mucous membranes.

When it is administered by the mucosal route, it may be applied, forexample, through the buccal mucosa, the nasal mucosa or the vaginalmucosa.

When the micronized film-forming powder according to the invention isadministered by the transdermal route, it will have a systemic effectand/or a local effect according to the nature of the active substanceand the other components present in the powder.

Advantageously, the composition according to the invention, comprisingthe micronized film-forming powder, exists in a pulverizable dry form.This allows easy delivery of a precise dose.

The invention also relates to a process for the preparation of amicronized film-forming powder.

All the processes known to persons skilled in the art may be used in thecontext of the production of this micronized film-forming powder.

There may be mentioned, as an example of a method for preparing a powderwet or dry granulation, by extrusion, by atomization followed bymicronization in order to obtain a micronized powder.

Or according to another embodiment, the active substance is micronizedand then mixed with the excipients in powdered form, and the mixturethus obtained is granulated, by wet or dry granulation before a new stepof micronization.

In every case, the method for manufacturing the micronized film-formingpowder of the invention must include a micronization step of the mixturecomprising the active substance, the biocompatible adhesive agent andthe plasticizer.

For the micronization, the conventional air jet method is used, forexample by using an air jet micronization equipment type ALPINE or JETMILL, in accordance with the manufacturer recommendations.

The preferred parameters for a micronization on a micronizer GALETTEAlpine 200AS are the following:

-   -   Injector: 7 to 8 Bars;    -   Crown: 4 to 6 Bars;    -   Speed: 25 kg/h.

In a particular test performed by the Applicant, before micronization,the powder had a grain mean size (particle size) of 110 μm. Aftermicronization, the resulting micronized film-forming powder had aparticle size of 3 μm.

The micronized film-forming powder according to the invention may beused with or in any device allowing its application on the surface of amoist or hydrated support, such as the mucous membranes or thepreviously hydrated dermis.

Thus, the invention also relates to any device for applying ordispersing the powder on the surface of a support, suitable for use incosmetic, pharmacy or nutraceutic.

The invention will be understood more clearly with the aid of figuresand the examples described below.

FIGURES

FIG. 1 illustrates the grain size distribution profile of the micronizedfilm-forming powder prepared in the example 2.

The right curve represents the grain size distribution profile beforemicronization. The left curve represents the grain size distributionprofile after micronization.

-   -   In abscissa: Particle size given in μm.    -   In ordinate: Volume, given as a percentage.

FIG. 2 illustrates the grain size distribution profile of the micronizedfilm-forming powder prepared in the example 3.

The right curve represents the grain size distribution profile beforemicronization. The left curve represents the grain size distributionprofile after micronization.

-   -   In abscissa: Particle size given in μm.    -   In ordinate: Volume, given as a percentage.

EXAMPLE 1 Micronized Film-Forming Powders According to the Invention

Four powders, each having the following composition by weight, areprepared: TABLE 1 Components Quantity in % Buprenorphine 3Microcrystalline 67 cellulose Kollidon ® VA64 10 Ethylcellulose 20

TABLE 2 Components Quantity in % 17β-Estradiol 5 Microcrystalline 55cellulose Kollidon ® VA64 10 Ethylcellulose 20 Dibutylphthalate 10

TABLE 3 Components Quantity in % Molsidomine 7 Eudragit ® RSP0 30Polyvinyl alcohol 3 Microcrystalline cellulose 50 Triethyl citrate 10

TABLE 4 Components Quantity in % Salbutamol 5 HPMC Succinate acetate 30Carbopol ® 974 PNF 3 Microcrystalline cellulose 51 Triethyl citrate 10Sodium lauryl sulfate 1

The various components are mixed in a mixer-granulator of themixer-granulator-vacuum drier type ROTOLAB ZANCHETTA or equivalent untilthe mixture is homogenized. Next, a wetting solution or suspension isincorporated, with stirring, in order to obtain a wet granulate.

This granulate is then dried under suitable conditions so as toevaporate the granulation solvent. This granulate is then calibrated.

EXAMPLE 2 Micronized Film-Forming Powder According to the Invention

A powder having the composition by weight described in detail in thetable 5 below is prepared. TABLE 5 Components Quantity in %Buprenorphine 3 Hydroxypropyl methyl cellulose 43.65 Carbopol 974P NF43.65 Eudragit RSPO 9.7Manufacturing Process

The various components are mixed in a mixer-granulator of themixer-granulator-vacuum drier type ROTOLAB ZANCHETTA or equivalent untilthe mixture is homogenized. Next, a wetting solution or suspension isincorporated, with stirring, in order to obtain a wet granulate.

This granulate is then dried under suitable conditions so as toevaporate the granulation solvent and then calibrated and micronizedwith a micronizer type GALETTE Alpine 200AS by using the followingparamaters:

-   -   Injector: 8 Bars;    -   Crown: 4 Bars;    -   Speed: 25 kg/h.        Final Product Control        Particle Size:

Carried out by using a laser granulometer MASTER SIZER 2000 equippedwith a vibrator Scirocco 2000.

Result: mean particle size: before micronization=559.133 μm; aftermicronization=54.242 μm.

Relative Humidity Level Measurement

Carried out by using a humidity analyser MA 30 Sartorius

Parameters: mass of the sample=3 9, Temperature=100° C., Desiccationtime=15 min

Result: Relative humidity=5.98%

Thickness Measurement

Procedure

Film manufacturing: 200 mg±20 mg of powder are deposited on a glasscoverslip (dimension 50×25 mm) with the aid of a screen of 500 μm insuch a way that a regular thin film is obtained. A gelose based on agarand artificial saliva (1.5/98.5 w/w) contained in a Petri dish isapplied with a light pression on the glass coverslip; an instantaneoushydration of the powder and a film formation are occurring. After 1 minof hydration, the film is removed and the thickness is monitored with athickness controller Braive Instrument®.

Results: 5 measurements are made at various points of the film on 3different films. Mean thickness=252.6 μm

Tack Measurement

This test is similar to the so-called “Probe Tack” one—ASTM standard D2979, it is carried out by using a traction equipment.

Procedure: about 30 mg of powder are deposited on porcine mucousmembrane having a surface of 180 mm² previously moistened withartificial saliva and fixed on a glass plate. Another mucous membrane ofan equivalent surface previously moistened with artificial saliva isfixed on a needle which compress the film-forming powder positionedbelow the equipment, and through the use of a force sensing device, thepeel strength from the mucous membrane of the formed film (Cf. Schemabelow) is measured.

Parameter:

-   -   Compression speed=50 mm/min    -   Compression force 20N    -   Time for maintaining the force=1 min    -   Traction speed=50 mm/min        Result:

Mean force of tack=3.3N (∂=0.8)

Resistance to Liquid Tests—Measurement of the Contact Angle Formed by aLiquid at the Time t

Procedure:

Film manufacturing: 200 mg±20 mg of powder are deposited on a glasscoverslip (dimension 50×25 mm) with the aid of a screen of 500 μm, insuch a way that a regular thin film is obtained. A gelose based on agarand artificial saliva (1.5/98.5.w/w) contained in a Petri dish isapplied with a light pression on the glass coverslip; an instantaneoushydration of the powder and a film formation are occurring.

Sample cutting: with a scalpel, a gelose/film cut is carried out inorder to perform the measurement.

Measuring device used: instrumented Goniometer KRUSS G2

Effected measurements at t=15 s, t=30 s, t=60 s

Number of measurements effected: 10

Tested liquids: Mineral water at 22° C., Coca-Cola at 22° C., Sodiumbicarbonate solution at 22° C., Mineral water at 40° C.

Results: TABLE 6 Tested Liquid t = 15 s t = 30 s t = 60 s Mineral water22° C. 104° 93° 82° Mineral water 40° C.  76° 68° 54° Coca-cola 22° C.103° 91° 81° Sodium bicarbonate 22° C.  89° 73° 63°

A decrease of the contact angle in the course of the time is observedbut there is no complete absorption of the liquid whatever the pH of theliquid (acid, basic or neutral), the film is semipermeable.

EXAMPLE 3 Micronized Film-Forming Powder According to the Invention

A powder having the composition by weight described in detail in thetable 7 below is prepared. TABLE 7 Components Quantity in % 17β-Estradiol 5 Hydroxypropyl cellulose 53.2 Carbopol 974P NF 32.3Eudragit RSPO 9.5Manufacturing Process

The various components are mixed in a mixer-granulator of themixer-granulator-fluidized air bed drier equipped with a top spray,nozzle or equivalent until the mixture is homogenized. Next, a wettingsolution or suspension is sprayed with a spraying nozzle on the movingproduct in order to simultaneously distribute homogeneously the solutionand to dry it for evaporating the granulation solvent.

This granulate is sized and then micronized with a air jet micronizationdevice of GALETTE ALPINE 200 AS type, according to the followingparameters:

Injector 7 bars; Crown: 6 Bars; Speed: 25 kg/h.

Final Product Controls

Particle size: carried out using a laser granulometer MASTER SIZER 2000equipped with a vibrator Scirocco 2000.

Result: mean particle size before micronization=118.581 μm; aftermicronization=10.610 μm.

Thickness Measurement:

Procedure:

identical to the thickness measurement of the example 2

Results: 5 measurements are made at various points of the film on 3different films. Mean Thickness=254.9 μm

Relative Humidity Level Measurement

Carried out by using a humidity analyser MA 30 Sartorius

Parameters: sample mass=3 g, Temperature=100° C., dessication time=15min

Result Relative humidity 3.44%

Tack Measurement:

Procedure:

identical to the tack measurement of the example 2

Result

Mean force of tack 3.4N (∂=0,4)

Resistance to Liquid Tests—Measurement of the Contact Angle Formed by aliquid at the Time t

Procedure:

Identical to the resistance to liquid tests described in the example 2

Results: the results are represented in the table 8 below. TABLE 8Tested Liquid t = 15 s t = 30 s t = 60 s Mineral water 22° C. 58.5°  45° 37° Mineral water 50° C. 64° 52° 44° Coca-cola 22° C. 86° 73° 64°Sodium bicarbonate 22° C. 69° 64° 62°

While the contact angle decreases significantly in the course of thetime, the liquid is not totally absorbed by the adhesive, the film issemipermeable.

1. Micronized film-forming powder having a particle size of at most 100μm and comprising the combination of at least an active substance, atleast a biocompatible adhesive agent and at least a plasticizer. 2.Micronized film-forming powder according to claim 1, characterized inthat the active substance is micronized.
 3. Micronized film-formingpowder according to claim 1, characterized in that it has a particlesize of at most 50 μm.
 4. Micronized film-forming powder according toclaim 1, which has a particle size of at most 20 μm.
 5. Micronizedfilm-forming powder according to claim 1, which further comprises atleast one compound selected from the group consisting of a surfactant, awetting agent, a binder, a retardant, a penetration enhancer, abioerodible diluent, a colorant, a flavor, a pH controlling agent and acombination of at least two of these compounds.
 6. Micronizedfilm-forming powder according to claim 1, wherein the active substanceis a member selected from the group consisting of estradiol and itsderivatives, norethisterone acetate, progesterone, testosterone,trinitrine, fentanyl, nitroglycerine, nicotine (S(−)-nicotine),scopolamine, clonidine, isosorbide dinitrate, levonorgestrel incombination with ethinylestradiol or with estradiol, androstanolone,alclometasone dipropionate, acetazolamide, acyclovir, adapalene,alclomethasone dipropionate, amcinonide, ameleine, bamethansulphate+escin, betamethasone valerate, betamethasone dipropionate,bufexamac, caffeine, calcipotriol monohydrate, cetrimonium bromide,clobetasol propionate, crilanomer, desonide, dexpanthenol, diclofenac,diflucortolone, valerate, difluprednate, diphenydramine hydrochloride,econazole nitrate, erythromycin, flumetasone pivalate, fluocinoloneacetonide, fluocinodine, fluocortolone, fluocortolone hexanoate,fluocortolone pivalate, hydrocortisone, hydrocortisone acetate,ibacitabin, ibuprofen, imiquimod, ketoconazole, ketoprofen, lidocaine,metronidazole, miconazole nitrate, minoxidil, niflumide acid,penciclovir, benzoyl peroxide, piroxam, iodinated povidone,promestriene, pyrazonibutasone, roxithromycin, sulphacetamide,triamconolone, tazarotene, tretinoin and isotretinoin, triclocarban,vidarabine monophosphate, β₃-adrenergic agonist, growth hormone,oxybutinin, buprenorphine, pergolide, estradiol+nestorone, nesterone,7α-methyl-19-nortesterone, mecamylamine (antagonist ofnicotine)+nicotine, salbutamol, selegiline, buspirone, ketotifen,lidocaine, testosterone+estradiol, ketorolac, eptazocine, insulin,α-interferon, prostaglandines, 17β-estradiol+norethindrone acetate,5-aminolevulinic acid, benzodiazepine alprozolam, diclofenac,fenoprofen, flubiprofen, ketoprofen, methyl phenidate, miconazole,piroxicam, bruprenorphine, alprozolam, dexmedetomidine, prazosin(α-adrenergic antagonist), gestodene+ethinylestradiol, alprostadil,tulobuterol (β-adrenergic agonist), ethinylestradiol+norelgestromin,ketorolac, physostigmine, lidocaine, medindolol (α-adrenergic agonist),rotigotine (D2 dopamine antagonist), ethinylestradiol+norethindroneacetate, thiatolserine, and a combination of at least two thereof. 7.Micronized film-forming powder according to claim 1, wherein the activesubstance is a member selected from the group consisting of anemollient, a moisturizing agents, a vitamins, complex of fruit and anamino acid, and an antioxidant agents.
 8. Micronized film-forming powderaccording to claim 1, wherein the active substance is a member selectedfrom the group consisting of a vitamins, an inorganic salt, and brewer'syeast.
 9. Micronized film-forming powder according to claim 1, whereinthe bioadhesive agent is a member selected from the group consisting ofethyl cellulose, methyl cellulose, carboxymethyl cellulose,carboxymethyl cellulose sodium, hydroxyethyl cellulose, hydroxypropylcellulose, hydroxypropyl methyl cellulose sodium, polyvinylpyrrolidone,a polyvinyl alcohol, polyisobutylene, polyisopropene, xanthan gum,locust bean gum, chitosan, chitosan chloride, a polycarboxylat, acarbomers acrylic/methacrylic acid copolymer, acrylic acid/acrylamidecopolymer, acrylic acid/methyl methacrylate copolymer, acrylicacid/polyethylene glycol copolymer, polyacrylic acid/butyl acrylatecopolymer, HEMA (2-hydroxyethyl methacrylate) copolymerized withPolymeg® (polytetramethylene glycol), Cydot® marketed by 3M (carbopolcombined with polyisobutylene), pectin (of low viscosity), polyethyleneoxide, methyl vinyl ether/maleic anhydride copolymer, tragacanth,monomethyl ether, monomethacrylate, drum dried waxy maize starch, sodiumstearyl fumarate, sodium hyaluronate, guar gum, sodium alginate, astarches, dextran and a mixture& thereof.
 10. Micronized film-formingpowder according to claim 1, wherein the plasticizer is a memberselected from the group consisting of dibutyl phthalate, dibutylsebacate, acetyltributyl citrate, acetyltriethyl citrate, tributylcitrate, tributylethyl citrate, triacetin, PEG, propylene glycol,glycerol, a glycerol monoester and a derivatives thereof, castor oil anda mixtures thereof.
 11. Micronized film-forming powder according toclaim 1, wherein the surfactant is at least one nonionic surfactants.12. Micronized film-forming powder according to claim 1, wherein thewetting agent comprises at least one polyol.
 13. Micronized film-formingpowder according to claim 1, wherein the binder is a member selectedfrom the group consisting of acacia, alginic acid, carboxymethylcellulose sodium, microcrystalline cellulose, a dextrin, ethylcellulose, gelatin, glucose, guar gum, hydroxypropyl methyl cellulose,methyl cellulose, polyethylene oxide, povidone, pregelatinized starchand a mixtures thereof.
 14. Micronized film-forming powder according toclaim 1, wherein the retardant is a member selected from the groupconsisting of hydroxypropyl methyl cellulose acetate or succinate,hydroxypropyl methyl cellulose, hydroxypropyl cellulose, ethylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose sodium, apolyvinyl alcohol, a hydrocolloid an alginate, guar gum, xanthan gum,gum Arabic, agar, dextrin, carragheenan, polyethylene oxide, a carbomer,a polymer and or copolymer of acrylic acid, of methyl methacrylate, ofpolyvinyl acetate, or of carboxymethyl acetate, and a mixtures thereof.15. Micronized film-forming powder according to claim 1, wherein thebioerodible diluent is a member selected from the group consisting ofcalcium or sodium carbonate or bicarbonate, sucrose, mannitol, xylitol,sorbitol, lactose, cellulose or microcrystalline cellulose powder,starch or a derivatives thereof, dibasic calcium phosphate, tribasiccalcium phosphate, calcium sulphate, a dextrat, a dextrin, a dextroseexcipient, fructose, kaolin, lactitol and a mixtures thereof. 16.Micronized film-forming powder according to claim 1, wherein thepenetration enhancer is a member selected from the group consisting ofan aliphatic fatty acid esters a fatty acid, an alcohol or polyol, analpha-hydroxy acids and a mixture thereof.
 17. Pharmaceutical, cosmeticor nutraceutical composition comprising a micronized film-forming powderaccording to claim 1 forming a film after application in situ on ahydrated support.
 18. A method which comprises administering acomposition according to claim 17, by the mucosal route.
 19. A methodwhich comprises administering a composition according to claim 17, onbuccal mucosa, nasal mucosa or vaginal mucosa.
 20. A method whichcomprises administering a composition according to claim 17, by thetransdermal route with local or systemic effect.
 21. Compositionaccording to claim 17, characterized in that it is in pulverizable form.22. Micronized film-forming powder according to claim 9 wherein thecarbomer is carbopol.
 23. Micronized film-forming powder according toclaim 11 wherein the nonionic surfactant comprises at least one memberselected from the group consisting of polyoxyethylene sorbitan (fattyacid ester), polyoxyethylene alkyl ether, and polyoxyethylene derivedfrom castor oil.
 24. Micronized film-forming powder according to claim12 wherein the polyol comprises at least one member selected from thegroup consisting of sorbitol, glycerin, and polyethyleneglycol. 25.Micronized film-forming powder according to claim 14 wherein thehydrocolloid is a pectin.
 26. Micronized film-forming powder accordingto claim 16 wherein the aliphatic fatty acid ester is isopropylmyristate; the fatty acid is oleic acid; and the alcohol or polyol isethanol, propylene glycol or polyethylene glycol.